Bisphenol A (BPA) is a common environmental endocrine disrupting chemical (EDC) with a range of potential adverse health effects. Growing epidemiologic and experimental studies have demonstrated a potential link between higher BPA exposure and cardiovascular diseases. In previous studies, we reported some of the first evidence on the arrhythmogenic actions of BPA in rodent hearts. We further showed that the pro-arrhythmic effects of BPA was shared by bisphenol S (BPS), a BPA analog that is used in many of the ?BPA-free? products. Our findings demonstrate the potential pro-arrhythmic toxicity of BPA, and highlight the need to further define the impact of BPA and related EDCs on human heart health. The goal of our proposal is to determine the pro-arrhythmic toxicity of BPA and BPS in larger animals, including humans, particularly through prolongation of the QT interval of the electrocardiogram (ECG). QT interval reflects the duration of ventricular excitation of the heart. In human and other larger species, a distinct arrhythmogenic mechanism is QT prolongation. Importantly, QT prolongation is a common forms of cardiac toxicity for chemical and pharmaceutical agents, and is well recognized as a central issue in cardiac safety. It has been shown that female sex hormones, including estrogen, prolong QT interval in both human females and animal models. However, the impact of BPA, a near ubiquitous estrogenic EDC, on the risk of QT prolongation and related arrhythmias is entirely unknown. Supported by compelling preliminary studies, we propose to address the central hypothesis that in the hearts of larger species including human, low-dose BPA and BPS have pro-arrhythmic toxicity through delay of ventricular repolarization and prolongation of the QT interval; this pro-arrhythmic action is particularly significant in hearts with existing QT prolongation, such as those of idiopathic long QT syndrome (LQT) patients. The study uses a combination of animal experiments using rabbits, and epidemiology analysis using biospecimens and data from the Fernald Community Cohort. The gender-specificity of the actions of the bisphenol chemicals will be addressed in each Aim. Three aims are proposed. The long-term (Aim 1) and rapid (Aim 2) effects of BPA and BPS exposure on cardiac electrophysiology and arrhythmogenesis will be examined using the rabbit model. In Aim 3, the correlation of BPA exposure in human adults and ECG markers of cardiac electrical abnormalities will be examined in the Fernald Community Cohort. The proposed research is significant because it is expected to provide important insights into the action and underlying mechanism of BPA and BPS on larger animal hearts. Further, our study will provide better understanding of the risk factors of cardiac arrhythmia, particularly in vulnerable subpopulations with cardiac disease. The Fernald Cohort study represents the first epidemiologic study on the association between BPA exposure and cardiac electrical abnormalities, bridging a major knowledge gap in our understanding of the toxicity of BPA.